The long-term goal of this proposed research is to develop a novel class of human SIRT1 inhibitors as potential treatment for cancer. Reversible protein acetylation plays critical roles in multiple important biological processes such as gene transcription, apoptosis, DNA repair, metabolism, aging, neurodegeneration, and HIV-1 replication. Protein deacetylation can be catalyzed by a class of evolutionarily conserved intracellular Sir2 family enzymes. In humans, seven Sir2 orthologues, i.e. SIRT1-7, have been identified. Interestingly, the gene expression and the deacetylase activity of SIRT1 are up-regulated in various human cancers. Pharmacological and genetic studies demonstrated that inhibition of the deacetylase activity of SIRT1 provides promising anti-cancer effect, which was further supported in studies on animal models of cancer. Therefore, SIRT1 deacetylase activity inhibition constitutes a novel anti-cancer therapeutic strategy. Even though several classes of SIRT1 inhibitors have been identified from efforts such as random chemical library screening, few of them exhibited potent and selective inhibitory profiles. There is thus an urgent need to develop new inhibitors for this important human enzyme. Based on the N?-thioacetyllysine-containing mechanism-based SIRT1 peptide inhibitor lead that has been identified in PI's laboratory, its macrocyclic peptidomimetic analogs will be synthesized and evaluated for their SIRT1 inhibitory potency and selectivity. Two different types of the peptide macrocycles will be incorporated into the designed peptidomimetic analogs. It is anticipated that potent and selective human SIRT1 inhibitor(s) will be identified from the completion of this proposed project. These compound(s) can also serve as the new lead for developing the next generation of human SIRT1 inhibitors as potential drugs for treating cancer. The identified compound(s) from the proposed project will also be valuable chemical tool(s) for further studying the SIRT1 biology. The implementation of this research project will create ample opportunities for training both graduate and undergraduate students in biomedical research. PUBLIC HEALTH RELEVANCE: The proposed project focuses on the development of the peptidomimetic human SIRT1 enzyme inhibitors. The proposed studies will help the development of novel anti-cancer therapeutics.